The Piezo1 hypothesis of renal anemia

Abstract

Erythropoietin deficiency is an extensively researched cause of renal anemia. The etiology and consequences of shortened red blood cell (RBC) life span in chronic kidney disease (CKD) are less well understood. Traversing capillaries requires RBC geometry changes, a process enabled by adaptions of the cytoskeleton. These changes are mediated by transient activation of the mechanosensory Piezo1 channel, resulting in calcium influx. Importantly, prolonged Piezo1 activation shortens RBC life span, presumably through activation of calcium‐dependent intracellular pathways triggering RBC death. Two Piezo1‐activating small molecules, Jedi1 and Jedi2, share remarkable structural similarities with 3‐carboxy‐4‐methyl‐5‐propyl‐2‐furanpropanoic acid (CMPF), a uremic retention solute cleared by the healthy kidney. We hypothesize that in CKD the accumulation of CMPF leads to prolonged activation of Piezo1 (similar in effect to Jedi1 and Jedi2), thus reducing RBC life span. This hypothesis can be tested through bench experiments and, ultimately, by studying the effect of CMPF removal on renal anemia.

The protein-bound uremic solute 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) increases erythrocyte osmotic fragility through interaction with the mechanosensitive channel Piezo1

“…(2022) that CMPF, at concentrations seen in patients with kidney failure, may act as an endogenous chemical activator of Piezo1 located on RBC surface and instigate eryptosis 15 . Our research presented herein provides the first evidence supporting this hypothesis.…”

“…(2022) recently observed that the active moiety of Jedi1/2 shows structural similarity with 3carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) (Figure 1), a uremic retention solute 15 . In CKD patients treated with hemodialysis, CMPF levels are increased 5-to 15-fold compared to healthy individuals 27 .…”

“…Recently, we have hypothesized that Ca 2+ influx through the mechanosensitive cation channel Piezo1 located in the RBC plasma membrane may be involved in the genesis of eryptosis 15 . Piezo1 plays a critical role in RBC volume regulation 16 , whereby shear stress in the microcirculation activates Piezo1-dependent Ca 2+ influx.…”

“…In CKD patients treated with hemodialysis, CMPF levels are increased 5-to 15-fold compared to healthy individuals 27 . Given this structural resemblance, Kotanko et al (2022) hypothesized that increased levels of CMPF lengthen the Piezo1 activation in a Jedi1/2-like fashion. The authors further hypothesized that this CMPF-induced activation might trigger a cascade of events that eventually results in eryptosis and shortened RBCLS 15 .…”

“…Given this structural resemblance, Kotanko et al (2022) hypothesized that increased levels of CMPF lengthen the Piezo1 activation in a Jedi1/2-like fashion. The authors further hypothesized that this CMPF-induced activation might trigger a cascade of events that eventually results in eryptosis and shortened RBCLS 15 . We explored the hypothesis that CMPF at a concentration seen in uremia activates Piezo1 located on RBC.…”